Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia

Methotrexate (MTX) is a key compound of chemotherapeutic regimens used in the treatment of childhood acute lymphoblastic leukemia (ALL). Resistance to this drug may arise by, among other factors, altered cellular uptake that may hamper the efficacy of the treatment. Recently, a G(80)A polymorphism has been described in the reduced folate carrier gene (RFC1), which encodes the major MTX transporter. Here, we assessed the association between the genetic polymorphisms G(80)A and both MTX plasma levels and childhood ALL outcome. Children with the A(80) variant had worse prognoses than patients with the GG genotype (P =.04), as shown by event-free survival estimates. Patients homozygous for A(80) had higher levels of MTX (P =.004) than the other genotype groups. Possible explanations for observed associations are discussed; however, additional experiments are required to achieve understanding of the underlying mechanism.     

High titer anti-HIV antibody reactivity associated with a paraprotein spike in a homosexual male with AIDS related complex

We observed a human immunodeficiency virus (HIV)-infected homosexual male with AIDS related complex (ARC) who had a serum globulin level of 80 g/L. Serum protein electrophoresis revealed a gamma globulin fraction of 40 g/L, of which 50% (20 g/L) was contained within a paraprotein spike, comprised predominantly of IgG kappa. This patient also had high titer anti-HIV antibodies in his serum, which were Western blot reactive at a final dilution of 1:500,000, and recognized gp120env, p66pol, p55gag, p53pol, p41gag, and p24gag. Because paraproteins in the past have been shown to be directed against specific antigens, we purified this patient's paraprotein using a modified high performance liquid chromatography (HPLC)-hydroxylapatite procedure and tested the purified paraprotein for anti-HIV antibody activity. The purified paraprotein retained anti-HIV antibody activity to a final dilution of 1:100,000, and recognized p66pol, p55gag, p53pol, p41gag, and p24gag. The recognition of both "gag" and "pol" gene products suggested that the purified paraprotein might not be monoclonal in origin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that the purified paraprotein contained at least two immunoglobulin light chain species (Mol wt 30 to 33 Kd). Affinity chromatography of the purified paraprotein using a p24- Sepharose 4B matrix separated the "gag" and "pol" antibody activities. Immunoglobulin gene rearrangement analysis of a bone marrow aspirate (which contained 15% plasma cells) failed to reveal a clonal population of immunoglobulin producing cells. We conclude that this patient's paraprotein accounted for most of the anti-HIV activity present in whole serum, and that this paraprotein was not monoclonal in origin.     

Murine tumor necrosis-inducing factor: purification and effects on myelomonocytic leukemia cells

The tumor necrosis-inducing factor (TNF) found in sera of Corynebacterium parvum-treated, endotoxin-stressed BALB/C and outbred albino CD-1 mice has been purified to a single band of protein by polyacrylamide gel electrophoresis after identification and removal of contaminating albumin and transferrin. This purified TNF has a molecular weight of 140,000, is glycoprotein in nature, and migrates on free electrophoresis as an alpha 2-globulin. TNF activity was continuously monitored during purification by bioassay in vitro (tumor cell lysis) and was confirmed by demonstration of induction of tumor necrosis in vivo. A single target tumor cell line, murine myelomonocytic leukemia (WEHI/3), was used in both assays. In the in vivo assay, controls were heat-inactivated samples of TNF. As additional controls, a line of TNF-resistant WEHI/3 cells was used in the in vitro assay. Results from in vivo radiolabeling of TNF-sensitive and TNF-resistant cells indicated a difference between their cytoplasmic peptide profiles. Optimal TNF production was not altered in C. parvum-endotoxin-treated mice by treatment with silica, a substance that is specifically toxic for macrophages. Exposure of mice to 650 rad whole-body radiation, which is not markedly damaging to macrophage elements in the reticuloendothelial system, completely abrogated the ability of the mice to produce TNF after C. parvum-endotoxin treatment. These findings suggest that in the sera of C. parvum-endotoxin-treated mice the protein that induces necrosis in tumors may not be of macrophage origin.     

The open abdomen. The Marlex mesh and zipper technique: a method of managing intraperitoneal infection

In conclusion, a zipper technique has been outlined that allows effective continuing drainage of the septic abdomen, permits early diagnosis of organ damage, is rapid and cost effective, minimizes ventilator dependency and gastrointestinal complications, is well tolerated by the patients, and has produced a modest 65 per cent survival rate in the first 34 critically ill patients in whom it was used. Selection of patients is critical. It is a technique that must not be undertaken lightly but that appears to have life-saving potential.     

Breast cancer screening and health behaviors among African American and Caribbean Women in New York City

A telephone-based survey regarding breast cancer screening practices among 300 African American and Caribbean women age 40 and over in New York City revealed that while U.S.-born women had significantly different sociodemographic profiles (in terms of insurance status, marital status, educational attainment), they were no more likely to have had a mammogram than the foreign-born women. Adjusting for insurance status and source of care, women with a provider recommendation were 8 times more likely ever to have had a mammogram (AOR 8.01, 95%CI: 3.74-17.14). Among foreign-born Caribbean women in the U.S. for less than half their lives, only 52% ever had a provider recommend a mammogram, compared with 77% of U.S.-born women. The findings confirm previous reports of the importance of physician recommendation in increasing mammography screening among urban Black women, and suggest that efforts to reach Caribbean-born women with breast cancer screening messages should emphasize the important role of providers.     

Viscum album agglutinin-I (VAA-I) induces apoptosis and degradation of cytoskeletal proteins in human leukemia PLB-985 and X-CGD cells via caspases: lamin B1 is a novel target of VAA-I

Viscum album agglutinin-I (VAA-I) is a potent inducer of cell apoptosis and possesses anti-tumoral activity. Using PLB-985 and chronic granulomatous disease (X-CGD) cells, which lack expression of gp91^phox, VAA-I was found to induce apoptosis in both cell lines as assessed by cytology, DNA laddering and degradation of the cytoskeletal protein gelsolin. Both cell lines expressed caspase-3 and -8 and VAA-I activated these caspases. We demonstrated that lamin B₁ is a novel target to VAA-I and its degradation was reversed by a pan-caspase inhibitor and by a caspase-6, but not a caspase-8, inhibitor.